Oxycodone (I) is produced by two principal methods:
a) Transformation of thebaine (II), a natural alkaloid isolated from the plant Papaver somniferum L., or its analogs (III), wherein R represents an alkoxy- or amino-alkyl residue. During this procedure (Scheme 1), thebaine (II) reacts in an acidic environment with hydrogen peroxide, peroxoacids or other oxidizing agents to form 14β-hydroxycodeinone (IV), which is hydrogenated to provide Oxycodone (I).

Thebaine, dissolved in hot concentrated acetic acid, is transformed to 14β-hydroxycodeinone by reaction with 30% hydrogen peroxide (Freund M., Speyer E.: J. Prakt. Chem. 94, 135 (1916); Lutz R. E., Small L : J. Org. Chem. 4, 220-233 (1939); DE 286431) with a ca. 30% yield. About the same yield was obtained also in oxidation of thebaine (II) with chromic acid (DE 286431; DE 411530) or with manganese acetate (Viebock F.: Chem. Ber. 67, 197 (1934)). A significantly higher yield (about 75%) was recorded when thebaine (II) was reacted with hydrogen peroxide in acetic acid at a temperature not exceeding 40° C. (Feldmann I. Ch., Liutenberg A. I.: Zh. Prikl. Khim. 18, 715 (1945)), or in a mixture of sulfuric acid and 88% formic acid (Krassnig R., Hederer Ch., Schmidhammer H.: Arch.Pharm. 329, 325 (1996)).
Comparable results were achieved when thebaine (II) was reacted with peroxoacids, for example m-chloroperbenzoic acid in a mixture of acetic acid and trifluoroacetic acid (Hauser F. M., Chen T-K., Carroll F. I.: J. Med. Chem. 17, 1117 (1974)); but Ijima et al. concluded that this reaction does not provide reproducible yields (about 25%) and a lot of undesirable products are formed (Iijima I., Rice K. C., Brossi, A.: HeIv. Chim. Acta 60, 2135 (1977)).
In a modified procedure, instead of thebaine (II) codeine (V) can be used, Scheme 2, which is first oxidized to codeinone (VI), which, by reaction with either acylating or alkylating agents, provides an enolether/ester VII (EP 889045, U.S. Pat. No. 5,869,669, U.S. Pat. No. 4,639,520), essentially a thebaine analogue, which is further gradually transformed to 14β-hydroxycodeinone (IV) by any of the above-mentioned methods.

It is also possible to classify the Sankyo process (GB 1,260,699) in this group, which process issues from codeinone (VI), which provides codeinone pyrrolidinylenamine (VIII) with pyrrolidine in aprotic solvents, Scheme 3. Subsequent reaction with hydrogen peroxide, chromic acid, organic peroxyacids (peracetic, perbenzoic) or permanganate, in the environment of aqueous acetic acid, phosphoric acid, etc., provides 14-hydroxycodeinone (IV).

b) Oxidation of codeinone (VI) by action of peroxoacids, of combination of organic acids and hydrogen peroxide, or of inorganic oxidizing agents (e.g. Co3+ salts), with a maximum yield of 57% of 14β-hydroxycodeinone, which is hydrogenated to Oxycodone (I) (Coop A., Rice K. C.: Tetrahedron 55, 11429 (1999)).
The C-7-C-8 double bond of 14β-hydroxycodeinone was hydrogenated catalytically according to CH 751 10 (U.S. Pat. No. 1,468,805) on Pt black, colloidal Pd, or in the presence of PdCl2 (U.S. Pat. No. 1,485,673) in diluted acetic acid. Ijima used Pd/BaSO4 as the catalyst in this reaction (J. Med. Chem. 21, 398 (1978)), as well as Lutz R. E. and Small L. (J. Org. Chem. 4, 220 (1939)); the use of 10% Pd/C in concentrated acetic acid has also been known (Krassnig R., Hederer Ch., Schmidhammer H.: Arch. Pharm. 329, 325 (1996)) with the yield of about 70%. Feldmann and Liutenberg (Zh. Prikl. Khim. 18, 715 (1945)) hydrogenated the hydrochloride of 14β-hydroxycodeinone on Raney-Ni in hot ethanol with the yield of 74% hydrochloride of Oxycodone.
All the mentioned methods of preparation of Oxycodone (I) have drawbacks that the reaction of peroxide/peroxoacids with thebaine or its analogues does not yield unambiguously reproducible results, a mixture of badly separable byproducts is formed, and the yields are low.
These drawbacks have been rectified by the method of the present invention.